The knowledge developed about the immune system in the twentieth century and today, has allowed its use in cancer treatment, scientists around the world indicate it has been possible to reactivate the immune system with immunotherapy, mainly from vaccines with which it has proven possible to block tumor cells and provide quality of life and survival to patients treated with such vaccines. It is also known that conventional treatments such as chemotherapy and radiotherapy do not “cure” cancer, but are palliative therapies with many side effects in almost all body systems, causing in turn what has been called the “second tumor” or metastasis and disease progression. Therefore, immunotherapy offers a new alternative in the treatment of cancer, because it does not generate the side effects of other treatments. Immunotherapy is regarded as the fourth treatment against cancer.
At present there are several known studies on cancer vaccines and some in which tumor antigens extracted through the serum of cancer patients are used, in order to boost the immune system and induce a specific immune response against tumor cells.
Each vaccine has certain components based on the type of vaccine desired: there are biological vaccines, synthetic, genetic, protein, antigen, dendritic cells, etc.
It is thought that the vaccine's action mechanism may include the inhibition of the enzyme collagenase which is employed by tumor cells to cause dissolution of collagen used by all cells to stick together. Another possible mechanism of action is that by increasing collagen concentration with the vaccine, the enzyme collagenase is inhibited and the metastasis to other organs by the tumor cells is blocked.
The vaccine is a biological compound intended to reactivate and stimulate immune system cells, B lymphocytes, T lymphocytes and NK cells to block the metastasis of tumor cells and reactivate the bone marrow depressed by the cancer itself and by conventional treatments, such as chemotherapy and radiotherapy
Currently research studies have been conducted that seek to determine the behavior of the immune system in order to search for alternatives in the fight against tumor cells. Among the state of the art documents related to the present disclosure are:
European patent application EP1523989 which discloses compositions and methods for treating and/or preventing cancer in an animal. Improvements are reported with the use of a yeast-based vaccine comprising a yeast vehicle and an antigen selected to generate a humoral immune response in the animal. Said vaccine comprises yeast vehicle and a fusion protein expressed by the yeast vehicle it comprises: at least one cancer antigen and a peptide bound to the N terminal cancer antigen. The peptide with an established amino acid sequence stabilizes the fusion protein expression in the yeast vehicle or prevents translational modifications of the expressed fusion protein.
For its part, publication WO2009/066824 discloses a prophylactic and immunological therapy vaccine comprising monocytes or immature myeloid cells (IMCs) loaded with the native NK cell ligand and an antigen for the prevention and treatment of cancer, more precisely a vaccine comprising IMC monocytes loaded with α-galactosylceramide and an antigen to generate specific immune response. The antigen is obtained from the tumor and is expressed by transduction from a recombinant virus (adenovirus, retrovirus, virus vaccinia, pox-virus, Sindbis virus). Among the antigens employed are Her-2/neu, proteinase 3, a gene associated with Wilm's tumor, and murinoglobulin, and others.
European patent application EP 1576966 provides a method for the preparation of a vaccine. The method includes: (1) analyzing a specific antigen of a particular pathogen; (2) obtaining a polynucleotide encoding a specific antigen, (3) obtaining a polynucleotide sequence having a sufficient difference from the polynucleotide, (4) preparing a vaccine using the polynucleotide sequence. The antitumor vaccine corresponds in particular to an EGFR molecular vaccine, prepared from an EGRF molecule as an antigen and proteins, genes, viruses or bacteria, stably transformed. One of the biological functions of the EGFR molecular vaccines is that they possess an antitumor effect on a variety of solid tumors in which the molecule EGFR is overexpressed, i.e., lung, breast, ovarian, colon, prostate and stomach cancers among others, further comprising a protective immunological effect and therapeutic inhibition of metastatis. The vaccine generates an active and passive immune response by the organism treated.
The publication WO 2004/007734 relates to constructed plasmids that express the human Her-2/neu gene and possess anticancer activity and a vaccine comprising the same for preventing and or treating cancer. The plasmids are used as vectors that encode tumor-associated antigens. The document mentions that they are easily generated and safe to administer. Such plasmids are prepared by inserting a truncated HER-2/neu gene lacking intracellular domain into a pTV2 or pCK plasmid. The plasmids additionally translate a cytokine gene. The vaccine then comprises the plasmids prepared, a pharmaceutically acceptable carrier and a cytokine gene.
Similarly, publication WO 2009/083202 relates to a parvovirus characterized by a CpG-enriched genome, wherein the genome contains at least 2 additional CpG inserts that are not present in the natural genome, and the use of a parvovirus based on parvovirus H1, Lu lll, tiny mouse virus (MMV), mouse parvovirus (MPV), tiny rat virus (RPV), rat virus (RV), vectors based on the above species and/or cells capable of actively producing the prior species for the preparation of a pharmaceutical composition for treating cancer, specifically pancreatic carcinoma, hepatoma or lymphoma.
U.S. Pat. Appl. Publ. 2009/0117081 discloses that parvoviruses such as adeno-associated type 2 virus (AAV2) are oncolytics, selectively mediating apoptosis in cancer cells and their precursors, while leaving healthy cells intact. It further discloses a pharmaceutical composition comprising these viruses and a vehicle.
Patent application EP 1523989 relates to a process for the preparation of an anticancer vaccine derived from serum or autologous leukocytes. The preparation method includes coagulating a defined amount of blood from a cancer patient who has not been treated with chemotherapy or radiotherapy, centrifuging said blood with a rotational speed of at least 2000 rpm for 30 seconds, combining the supernatant serum with an aqueous solution of formaldehyde at a temperature of at least 37° C. for at least 28 days, treating the product of the previous step with phosphoric acid, filtering, treating the precipitate with aqueous solution of hydrochloric acid to lower the pH to 4, centrifuging the product at a rotational speed of at least 2000 rpm, collecting the precipitate, treating and dissolving the precipitate with a buffer solution to raise the pH to a physiological value and repeating the last eight steps.
Spanish patent application ES2250226 claims the use of non-pathogenic parvoviruses for the preparation of a medicament for reducing the side effects of therapies with genotoxic agents in patients with chronic and/or consumptive reduction diseases, the reduction of side effects appearing with maintenance or increase of the genotoxic agents' dose and the side effects affecting hematological parameters.
Within the state of the art are also reports of investigations conducted by Dr. Matthias Rath related to the mechanisms cancer uses to expand through the body and particularly to the mechanism of the degradation of collagen.
While the prior art has sought solutions to the technical problem, which is to provide safe and effective therapeutic alternatives and without the side effects associated with chemotherapy and radiotherapy, there are still no biological vaccines which, from tumor-associated antigen (obtained from cancer patient serum) and adjuvants such as an attenuated DNA virus, and specifically a parvovirus and specific amino acids, would allow not only treating cancer without side effects but also inhibit metastasis and provide overall quality of life and survival.
In particular it is relevant to mention that none of the mentioned antecedences reports experimental results or clinical studies proving the effectiveness of the methods and vaccines in humans. By contrast, the effectiveness of the vaccine in the present disclosure has been demonstrated in humans as will be shown later in the examples. Therefore, the vaccine in the present disclosure provides the following improvements and advantages over conventional vaccines in the prior art:
1. It comprises the parvovirus genome (PVC-2), non-pathogenic and attenuated, containing genes to direct the production of 4 or 5 proteins, three of which form the viral capsid. These viruses which have only about 5000 nucleotides are easy to sequence, so it is possible to map nucleotides; from these proteins an active cellular immunity is produced.
2. It has an antigen which is extracted through the patient's own blood (autologous), whose tumor protein is overexpressed, which provokes a humoral immunity, with production of antibodies (Ab).
3. It will not cause damage to healthy cells, but will react specifically against tumor cells.
4. It will reactivate the bone marrow (red cells, white cells and platelets) depressed by cancer and traditional treatments, which has been shown in clinical studies. It has been shown it can reactivate defenses (B lymphocytes).
5. It has three amino acids as adjuvants that will block the enzyme collagenase and/or increase collagen degraded by tumor cells, to in turn regenerate tissue damaged by the cancer itself or by the conventional treatments applied.
6. In patients treated with chemotherapy and/or radiotherapy, the vaccine can decrease the side effects caused by such traditional treatments, improving the quality of life and survival of patients, which has been shown in clinical studies of patients treated in advanced stages of the disease.
7. Unlike other vaccines, it has been tested in humans in clinical phases I and II, showing a 98% safety in patients treated. Only mild side effects have been reported such as irritation at the site of vaccine application (not in all patients) and slight erythema that subsides after a few minutes.
8. The vaccine tested in humans in clinical phase II, unlike other vaccines presented, shows effectiveness in specific types of cancer such as malignant melanoma, breast cancer, prostate cancer and hematopoietic cancers, which is advantageous, as it not only allows obtaining an immune response of humoral type (Ac), but also produces an active specific cellular immunity against tumor cells, thanks to the components that constitute the vaccine.
9. In studies of stages I and II, it was shown that during the 24 months of study and treatment of patients, it could give most of them quality of life (Karnofsky) and survival, exceeding expectations given to patients with conventional treatments.